Review
Autoimmune encephalitis: clinical
1
Oxford Autoimmune Neurology
Group, Nuffield Department of
Clinical Neurosciences, Oxford,
UK
2
Department of Neurology,
Oxford University Hospitals NHS
Foundation Trust, Oxford, UK
Correspondence to
Prof Sarosh R Irani, Oxford
Autoimmune Neurology
Group, Nuffield Department of
Clinical Neurosciences, Oxford
University, Oxford, Oxfordshire,
UK; s​ arosh.​irani@n​ dcn.​ox.a​ c.​uk
Accepted 14 May 2021
Published Online First
9 June 2021
​pn.​bmj.​com
© Author(s) (or their
employer(s)) 2021. Re-­use
permitted under CC BY.
Published by BMJ.
To cite: Uy CE, Binks S,
Irani SR. Pract Neurol
2021;21:412–423.
spectrum and management
Christopher E Uy ‍ ‍ ,1,2 Sophie Binks ‍
ABSTRACT
Autoimmune encephalitis defines brain
inflammation caused by a misdirected immune
response against self-­antigens expressed in
the central nervous system. It comprises a
heterogeneous group of disorders that are
at least as common as infectious causes of
encephalitis. The rapid and ongoing expansion
of this field has been driven by the identification
of several pathogenic autoantibodies that
cause polysymptomatic neurological and
neuropsychiatric diseases. These conditions often
show highly distinctive cognitive, seizure and
movement disorder phenotypes, making them
clinically recognisable. Their early identification
and treatment improve patient outcomes,
and may aid rapid diagnosis of an underlying
associated tumour. Here we summarise the
well-­known autoantibody-­mediated encephalitis
syndromes with neuronal cell-­surface antigens.
We focus on practical aspects of their diagnosis
and treatment, offer our clinical experiences of
managing such cases and highlight more basic
neuroimmunological advances that will inform
their future diagnosis and treatments.
Introduction
Autoimmune encephalitis comprises a
group of disorders in which the host immune
system targets self-­antigens expressed in the
central nervous system (CNS).1 Some of the
best-­
characterised diseases are associated
with autoantibodies that target neuroglial
antigens (table 1). These autoantibodies
are considered pathogenic because they
are directed against the extracellular—and
hence in vivo exposed—domains of their
target antigens.2–4 This fundamental prop-
erty has led to much interest and excitement
surrounding this rapidly expanding field,
with new autoantibody targets described
most years. Many established antigens
are key synaptic proteins, ion channels or
receptors, meaning that the extracellular
domain-­targeting autoantibodies are likely
to directly modulate critical physiological
processes.
Uy CE, et al. Pract Neurol 2021;21:412–423. doi:10.1136/practneurol-2020-002567
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‍ ,1,2 Sarosh R Irani ‍ ‍ 1,2
This field is of major clinical impor-
tance to all neurologists because these
patients present with a wide variety
of neurological features and typically
respond to immunotherapies. Therefore,
these conditions are often considered ‘not
to miss’ diagnoses, with defined patho-
genic agents that can present to cognitive,
movement disorder, epilepsy, psychiatry
and peripheral nerve clinics.
In this pragmatic review, which reflects
our experience of managing >200 cases
with surface-­directed autoantibodies, we
highlight key clinical features to help
identify these patients, outline immuno-
logical findings that inform laboratory
testing and describe the clinically relevant
disease biology of relevance to treatment
decisions.
Autoimmune encephalitis is not rare
Until the discovery of neuroglial surface
autoantibodies, infections were the most
common known causes of encephalitis.
However, over the last 20 years, the
description of multiple autoantibodies
targeting the extracellular domains of
neuroglial proteins in patients with
encephalitis has shifted this balance. For
example, the California Encephalitis
Project found that among persons under
30 years of age, N-­ methyl-­D -­aspartate
receptor (NMDAR)-­antibody encephalitis
was more common than any individual
infectious cause of encephalitis.5 Also,
autoimmune causes of encephalitis have
been reported to be at least as common
as viral causes in Olmsted County, USA.6
Interestingly, the incidence of autoim-
mune encephalitis rose in the second
10-­year epoch of this study, likely owing
to growing awareness of these disorders
and more widespread diagnostic capaci-
ties. Nevertheless, as fever, focal neurolog-
ical deficits and cerebrospinal fluid (CSF)
lymphocytosis remain inclusion criteria
for many ‘all cause encephalitis’ studies,
such approaches likely continue to under-
estimate the prevalence of autoimmune
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 Table 1  Demographic, clinical and paraclinical features of neuronal autoantibody syndromes

2 of 14
Review

Neuronal auto-­
antibody (Ref.) and
predominant IgG Median age, years Sex ratio Immunotherapy response and
subclass (range) (M:F) Clinical features MR brain scan findings CSF findings EEG findings Other investigations outcomes
NMDAR10 25 43 56 21 1:4 Encephalitis 70%–80% normal or non-­ 80% abnormal 90% abnormal (slowing Ovarian teratoma in 60% of ~50% improve in 4 weeks with
IgG1 (2 months–85 years) with prominent specific, with a typical limbic (lymphocytic pleocytosis, most common, 20% adult, female patients. first line immunotherapy (IT).
polysymptomatic encephalitis in a minority. unpaired oligoclonal epileptiform abnormalities, After HSV encephalitis, ~70% of non-­responders improve
neuropsychiatric bands common). rarely extreme delta brush particularly children can develop soon after 2nd line IT.
presentation, polymorphic pattern). NMDAR (and other neuronal Improvement up to 24 months,
movement disorder, surface) autoantibodies. with 80% reaching mRS 0–2.
language disorder, 10%–15% relapse risk—reduced
autonomic dysfunction, by IT and tumour removal
coma and central apnoea. ~5% mortality.
LGI1*33 49 57 64 2:1 Limbic encephalitis with ~75% abnormal. ~25% abnormal (mild ~50% abnormal (~30% >90% with HLA-­DRB1*07:01. At 2 years, 1/3 fully recovered,
IgG4 (31–84) frequent focal seizures, ~40% increased signal/swelling pleocytosis with elevated epileptiform abnormal, Hyponatraemia common 1/3 functionally independent
including characteristic in medial temporal lobes protein). ~20% focal slowing). (~70%). but unable to work, 1/3 severely
facio-­brachial dystonic (unilateral >bilateral). disabled or dead.
seizures. Relapses in 20%–30%; associated
with poor outcomes.
CASPR2*30 49 55 66 9:1 Main syndromes: ~30% increased signal in medial ~30% abnormal ~70% abnormal (40% HLA-­DRB1*11:01. ~50% with good or full response
IgG4 (25–77) peripheral nerve temporal lobes. (pleocytosis, elevated epileptiform abnormal). Thymoma in ~20% (often with to tumour therapy/IT.
hyperexcitability, limbic protein±oligoclonal LGI1 antibodies in addition) ~45% with partial IT response.
encephalitis and Morvan’s bands). Electromyography may ~25% relapse.
syndrome. demonstrate hyperexcitability
(fasciculations, myokymia).
GABAAR20 21 40 1:1 Encephalitis with frequent >80% cortical and subcortical 25–50% lymphocytic >80% abnormal Thymoma ~30%. IT-­responsive, however, mortality
IgG1 (2 months–88 years) status epilepticus. FLAIR signal abnormalities pleocytosis±oligoclonal (encephalopathy with ictal due to status epilepticus or related
involving 2+ brain regions. bands and elevated abnormalities). complications ~10–20%.
protein.
GABABR22 61 1.5:1 Limbic encephalitis with ~70% abnormal (45% increased ~80% lymphocytic ~75% with ictal Tumours in ~50% ~90% show response to IT, those
IgG1 (16–77) prominent seizures. signal in medial temporal lobes. pleocytosis. abnormalities. (mostly SCLC). with tumour have poorer prognosis
with recurrent neurological
symptoms and higher mortality.
AMPAR58 Mean 53.1 2:1 Limbic encephalitis with ~85% abnormal (67% with ~70% abnormal. 45% abnormal. Tumour identified in ~70% Most patients showed
(14–92) prominent confusion, bilateral mesial temporal (thymus, SCLC, breast, ovary). improvement from peak of disease,
amnesia, seizures and involvement). median mRS=1 in survivors.
psychiatric/behavioural ~15% of reported patients died
symptoms. (commonly due to complications
from malignancy).
DPPX27 53 1.5:1 Multifocal encephalitis 100% normal or non-­specific. ~30% abnormal (mild ~70% abnormal (focal or ~10% with B-­cell neoplasm 60%–70% improve with IT.
(13–76) with myoclonus, tremors pleocytosis and elevated diffuse slowing). (gastrointestinal follicular
and hyperekplexia, protein). lymphoma, ; leukaemia).
prominent diarrhoea/
weight loss.
Continued

Uy CE, et al. Pract Neurol 2021;21:412–423. doi:10.1136/practneurol-2020-002567

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 Table 1  Continued
Neuronal auto-­
antibody (Ref.) and
predominant IgG Median age, years Sex ratio Immunotherapy response and
subclass (range) (M:F) Clinical features MR brain scan findings CSF findings EEG findings Other investigations outcomes
GlyR28 50 1:1 3 main syndromes: Brain: temporal lobe ~40% pleocytosis, 20% ~70% abnormal EMG abnormal 60% ~10% mortality in initial case
IgG1/3 (1–75) stiff-­person spectrum inflammation in 5%, abnormal oligoclonal bands. (55% diffuse slowing, 15% (continuous motor unit series.
disorder ~30%, mostly non-­specific. focal epileptic abnormal, 5% activity, spontaneous or Good outcomes in survivors with
PERM (progressive Cord: ~20% (mostly short/ focal slowing). stimulus-­induced activity, median mRS=1 at latest follow-­up.
encephalopathy with patchy lesions, 5% longitudinally neuromyotonia) Duration of follow-­up 18 months–7
rigidity and myoclonus extensive lesion). Thymoma in 15%. years, 82% treated with IT.
limbic encephalitis).
MOG17–19 59 37 1:1 Optic neuritis, transverse Brain: ~75% abnormal (bilateral ~60% lymphocytic Not reported. Visual evoked potentials may ~75% have good response to
(1–74) myelitis, brainstem poorly demarcated subcortical pleocytosis oligoclonal show evidence of previous optic corticosteroids.
encephalitis, encephalitis. lesions), ~30% brainstem bands uncommon. neuritis. ~60% make a full or good
involvement. recovery.
Cord: ~50% abnormal, mixed Relapses are common.

Uy CE, et al. Pract Neurol 2021;21:412–423. doi:10.1136/practneurol-2020-002567

STM/LTM with frequent conus
medullaris involvement.
Orbit: extensive, often bilateral,
optic nerve lesions with frequent
chiasmal involvement.
IgLON532 60 64 1:1 4 main syndromes: ~80% normal/ non-­specific. 30% CSF pleocytosis. Not reported. HLA-­DRB1*10:01/HLA-­ Up to 50% respond to initial IT
IgG1/4 (46–83) sleep disorder (REM and ~15% brainstem atrophy. 50% elevated protein DQB*05:01 alleles in 87%. but far fewer have a sustained
NREM parasomnias, sleep 5% bilateral hippocampal (mean 64 mg/dL, No history of autoimmunity or response.
apnoea) atrophy. 52–192). cancer in 91%. Response better with combination
Bulbar syndrome ~10% unpaired therapy vs monotherapy (67% vs
Progressive supranuclear oligoclonal bands. 32%) and better for second-­line vs
palsy-­like syndrome first-­line therapy (59% vs 32%).
Cognitive
syndrome±chorea.
Neurexin-3α61 44 1:2 Encephalitis. 20% mesial temporal T2/FLAIR 100% abnormal Not reported   40% mortality despite IT, remaining
(23–57) signal abnormal. (pleocytosis, elevated Ig 60% partial recovery in initial
index). series.
*LGI1-­antibodies and CASPR2-­antibodies were historically classified as antibodies against the Voltage-­Gated Potassium Channel.
AMPAR, α-amino-3-­hydroxy-5-­methyl-4-­isoxazolepropionic acid receptor; CASPR2, contact-­associated protein 2; CSF, cerebrospinal fluid; DPPX, dipeptidyl peptidase-­like protein 6; EEG, electroencephalogram; GABAA/BR, gamma aminobutyric acid; GlyR, glycine receptor;
HSV, herpes simplex virus; IgLON5, immunoglobulin-­like cell-­adhesion molecule 5; IT, immunotherapy; L, long-­segment; LGI1, leucine-­rich glioma inactivated protein 1; MOG, myelin-­oligodendrocyte glycoprotein; mRS, modified Rankin score; NMDAR, N-­methyl-­D-­aspartate
receptor; (N)REM, (non)-­rapid eye-­movement sleep; S, short-­segment; SCLC, Small Cell Lung Cancer; TM, transverse myelitis.
Review

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 Review
causes, which often lack these features.7 In future, we
predict that unbiased surveys in patients with enceph-
alitis will show that the growing range of autoimmune
causes significantly exceed those of infectious causes in
developed countries.
Distinctive clinical manifestations of individual
autoimmune encephalitides
While the clinical features of these disorders span the
spectrum of neurological symptomatology, for patients
with autoantibodies against any individual target there
is often a characteristic set of core phenotypic mani-
festations, which may relate to the regional expres-
sion, function and relative susceptibility of the target
protein. Table 1 summarises the most common such
syndromes on a ‘per target’ basis.
By way of generalisation, autoantibody-­ mediated
disorders often present rapidly, over a few days to
weeks. However, we have observed more chronic
courses, of between 1 and 5 years, particularly in
leucine-­rich glioma-­ inactivated protein 1 (LGI1)-­
antibody, contact-­ associated protein 2 (CASPR2)-­
antibody and immunoglobulin-­ like cell-­adhesion
molecule 5 (IgLON5)-­ antibody syndromes. These
findings mean that time to disease nadir is often
outside of the 3-­ month duration which appears in
diagnostic guidelines.8 In our clinical experience,
these more insidious courses—which are sometimes
more akin to neurodegenerative presentations than
florid encephalitis syndromes—often lead to a delayed
diagnosis, and hence late commencement of immuno-
therapy. In patients with more acute-­onset, dramatic
presentations the diagnosis tends to be considered
early but immunotherapy may still be delayed while
excluding differentials and awaiting autoantibody test
results. While tumours, prion disease and metabolic
disorders are often in the differential diagnosis, a prag-
matic trial of immunotherapy may only be absolutely
contraindicated in the setting of some infections. Yet,
observational data show that corticosteroids may be
beneficial in some forms of herpes simplex virus (HSV)
encephalitis, suggesting this may not be a universal
contraindication.9
To encourage earlier immunotherapy administra-
tion to these patients, we have set out below some
‘identifying’ clinical findings that we find valuable in
everyday autoimmune neurology practice (figure 1).
Some features are so characteristic of certain antibody
syndromes that they serve as essentially pathogno-
monic clues to the underlying autoantibody. Later, we
describe the dominant presenting features, and relate
these to individual syndromes.
Psychiatric/behavioural
Psychiatric symptoms such as aggression, irritability,
mood lability, hallucinations and marked disturbance in
sleep/wake cycles may occur in many of these patients
across the spectrum of autoimmune encephalitis,
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Figure 1  Classic syndromes and characteristic features of
neuronal autoantibodies. Listed in an estimated order of
descending frequency. AMPAR, α-amino-3-­hydroxy-5-­methyl-
4-­isoxazolepropionic acid receptor; CASPR2, contact-­associated
protein 2; DPPX, dipeptidyl peptidase-­like protein 6; GABAA/
BR, gamma aminobutyric acid; IgLON5, immunoglobulin-­like
cell-­adhesion molecule 5; LGI1, leucine-­rich glioma inactivated
protein 1; NMDAR, N-­methyl-­D-­aspartate receptor; MOG,
myelin-­oligodendrocyte glycoprotein.
and are especially notable in NMDAR-­antibody and
α-amino-3-­h ydroxy-5-­m ethyl-4-­i soxazolepropionic
acid receptor-­antibody syndromes.
In adult-­onset NMDAR-­antibody encephalitis, psychi-
atric features are typically the presenting complaint, with
patients often needing mental health assessments before
a neurology consultation. In our experience, relatively
isolated psychiatric features occur in these patients only
at disease onset. Subsequently, within a few days, they are
rapidly accompanied by more traditional neurological
abnormalities including delirium, amnesia and seizures.
Nevertheless, careful consideration of the psychopa-
thology can help in differentiating NMDAR-­ antibody
encephalitis from primary psychiatric disease. NMDAR-­
antibody encephalitis often presents with a complex
phenotype spanning classically distinct psychiatric diag-
nostic categories, including domains of mood, psychosis,
behaviour and catatonia, the latter also seen with gamma
aminobutyric acid A receptors (GABAAR)-­antibodies.10
By contrast, early ‘transdiagnostic’ presentations are
unusual in most primary psychiatric diseases. Overall, the
complex psychiatric phenotype at onset combined with
polysymptomatic neurological disease and a polymor-
phic movement disorder, discussed in detail later, creates
a multifaceted presentation highly characteristic of
NMDAR-­antibody encephalitis. These features contrast
markedly to the poorly circumscribed clinical syndrome of
neuropsychiatric systemic lupus erythematosus, in which
NMDAR-­antibodies have also been reported. However,
by contrast to antibodies which target native neuronal
surface epitopes, those from patients with neuropsychi-
atric systemic lupus erythematosus have been found to
Uy CE, et al. Pract Neurol 2021;21:412–423. doi:10.1136/practneurol-2020-002567

show intrinsic ‘stickiness’, which is not NMDAR-­specific,
and hence have limited diagnostic value.11
Cognition
In the acute phase, many patients with encephalitis
show disorientation, confusion, confabulation and
amnesia, features that may relate to the dense expres-
sion of many autoantigens in limbic structures, partic-
ularly the hippocampus. Patients with LGI1-­antibody
and NMDAR-­antibody syndromes, and other forms of
limbic encephalitis, often experience a dense amnesia
for the period of acute hospitalisation, especially the
nadir of their disease. Some patients and relatives
consider this fortuitous due to several, inevitably
distressing, events typical of their hospital stays. In
LGI1-­antibody encephalitis, the amnesia characteristi-
cally affects both anterograde memories plus a loss of
autobiographical retrograde epochs.12 13 Comparative
neuropsychological analyses are pending in the other
forms of autoimmune encephalitis.
Seizures
Seizures occur in most autoimmune encephalitis
syndromes and are a common factor that triggers
neurological attention. The types and frequencies of
seizure vary between autoantibody-­mediated diseases
and may help pinpoint the individual autoantibody.
In LGI1-­antibody encephalitis, the seizure profile is
especially well-­characterised. These patients, typically
men in their fifth to eighth decades, have very frequent
focal events with multiple semiologies and only rare
generalised seizures. The pathognomonic faciobra-
chial dystonic seizures are frequent, brief events with
posturing of the ipsilateral face and arm that often
occur hundreds of times per day.14 15 Also, the leg may
be involved and the sudden leg spasms often precip-
itate falls. In addition, patients with LGI1-­antibodies
may have short-­lived, and again frequent, piloerection
seizures and experience paroxysmal dizziness spells.16
From our experience, paroxysmal dizziness spells are
likely ictal events characterised by frequent, intense
episodic dizziness without vertigo or electroenceph-
alographic correlates. In these patients, other focal
seizure semiologies include more classical temporal
lobe events, with rising epigastric phenomenon,
sudden onset fear or panic, and déjà-vu or jamais-­vu.
As many of these are very short lived, they may be
subtle and their detection often requires direct ques-
tioning of patients and relatives.
Although not as well-­ characterised as the seizures
associated with LGI1-­ antibodies, CASPR2-­ antibody
encephalitis is also associated with frequent focal seizures
and rare generalised seizures.16 However, we have not
observed faciobrachial dystonic seizures and paroxysmal
dizziness spells in the CASPR2-­antibody patients, whose
seizure semiology awaits further characterisation.
Myelin oligodendrocyte glycoprotein (MOG)
antibodies are associated with relapsing syndromes
Uy CE, et al. Pract Neurol 2021;21:412–423. doi:10.1136/practneurol-2020-002567
Review
involving brainstem or cortical encephalitis, some-
times with optic neuritis and transverse myelitis, which
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particularly involve children and young adults. Seizures
may present as the index event and the syndrome can
evolve to a more diffuse encephalitis, including one
which radiologically mimics classical acute dissemi-
nated encephalomyelitis. Patients typically respond
well to corticosteroid therapies, although the dura-
tion of their administration remains controversial as
relapses are common.17–19 This presentation is rare; in
our practice, we have seen one case of MOG-­antibody
related encephalitis alongside >200 other patients
with autoimmune encephalitis.
Status epilepticus may occur in autoimmune enceph-
alitis and is most frequent in patients with antibodies
to the GABAAR/GABABR. Patients with GABAAR-­
antibody encephalitis frequently have distinctive
neuroimaging with cortical and subcortical T2/FLAIR
signal on MRI affecting two or more brain regions.20
21
In our experience, these multiple ‘fluffy’ lesions
appear to be a characteristic feature; their presence
consistently associated with GABAAR-­antibody posi-
tivity. Patients with GABABR-­antibodies are typically
in around their sixth decade of life and commonly
present with an acute limbic encephalitis. More rarely,
they have a prolonged time course, characterised as a
rapidly progressive dementia.22 Detection of GABABR-­
antibodies should prompt a search for malignancy,
with tumours in ~50% of patients (most commonly
small cell lung cancer).
Although patients with NMDAR-­antibody enceph-
alitis often have few seizures, it is sometimes an ictal
event that prompts consideration of diagnoses outside
the realm of primary psychiatric disease.
One important question is whether testing these
autoantibodies benefits a broader population of
people with epilepsy. To date, studies have yielded
highly divergent positivity rates for autoantibodies
in a variety of patients with seizures. However, only
recently have studies combined accurate clinical
phenotyping with the autoantibody results in unse-
lected populations.23 24 These largely concur with our
routine clinical experience: patients who have unse-
lected new-­onset seizures, neuronal surface autoanti-
bodies and an immunotherapy-­responsive syndrome
typically have mild features of autoimmune enceph-
alitis, such as cognitive and mood features, specific
seizure semiologies, dysautonomia and limbic MRI
changes. This clinically-­ driven assessment approach
aims to limit unfruitful or equivocal immunotherapy
trials in patients attending epilepsy clinics.
Movement disorders
The autoimmune encephalitis syndromes may show
a diverse spectrum of movement disorder phenom-
enologies. In keeping with the complex nature of
NMDAR-­antibody encephalitis, the associated move-
ment disorder is typically polymorphic, defying
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 Review
classification into classical movement disorder taxono-
mies.25 26 Most characteristically, patients have combi-
nations of chorea, stereotypies and dystonia, with
limited tremor, which affect all limbs and—most char-
acteristically—the face and mouth.
Encephalitis syndromes associated with both glycine
receptor (GlyR) and dipeptidyl peptidase-­like protein
6 (DPPX) antibodies are characterised by hyperek-
plexia and myoclonus;27 28 however, accompanying
features, such as marked rigidity and falls in GlyR-­
antibody encephalitis and prominent diarrhoea in
DPPX-­antibody encephalitis, can usually differentiate
these entities. Although not typically associated with
a movement disorder, chorea is rare in LGI1-­antibody
encephalitis.29
Gait disturbances are frequent in CASPR2- and
IgLON5-­antibody syndromes.30–32 IgLON5-­antibody
disease is associated with a polymorphic sleep distur-
bance plus progressive supranuclear palsy-­like picture
with axial rigidity and gait freezing, whereas CASPR2-­
antibody disease typically has a gait disturbance
secondary to episodic or persistent ataxia. Indeed,
ataxia helps to differentiate CASPR2- from LGI1-­
antibody syndromes but, as with psychiatric features
and seizures, is rarely the sole clinical manifestation.
Dysautonomia
Dysautonomia is a common feature to many of these
disorders. These symptoms are typically progressive
through the initial disease course and can be life-­
threatening, requiring close monitoring. Particularly
in NMDAR-­antibody encephalitis, wide fluctuations
in blood pressure and tachy-­ arrhythmias or brady-­
arrhythmias are key features that often prompt us to
consult with colleagues in intensive care and cardi-
ology. Occasionally, temporary pacing is appropriate.
Other autonomic involvement includes orthostatic
hypotension, constipation and abnormal sudomotor
function.
Pain
In our experience, pain is under-­recognised in the
autoimmune encephalitis syndromes particularly
in patients with autoantibodies to CASPR2. In this
disease, ~60% of patients report pain.16 30 It can
occur in the context of a peripheral nerve hyperex-
citability syndrome (neuromyotonia, fasciculations,
cramps and myokymia) but—more commonly—
develops without peripheral motor nerve involvement
(Ramanathan, Uy, Bennett and Irani, in revisions).
Pain is also less common with LGI1-­ antibodies.16
33
In addition, patients with GlyR-­antibodies often
complaint of allodynia, dysaesthesia and prominent
pruritus.28 In all these groups, our experience is that
pain may respond partially to immunotherapy but
often persists. This area merits more detailed future
studies.
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Differential diagnoses
Clinicians need to consider a broad differential diag-
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nosis to reflect the spectrum of neurological phenome-
nology in autoimmune encephalitis. Here we outline a
few considerations that apply in each of several clinical
situations.
►► Infectious encephalitis (most commonly HSV): often
presents with seizures as well as fever, focal neurology
and more extensive imaging changes than in autoim-
mune encephalitis.
►► Temporal lobe glioma in cases with mesial temporal
swelling: semiologies can overlap but autoimmune
encephalitis usually has a less abrupt onset and interval
imaging swelling on imaging typically resolves with
treatment on interval imaging.
►► Creutzfeldt-­ Jakob disease and other rapid dementias:
often remain a differential in more chronic cases, espe-
cially patients with LGI1-­antibodies. However, in prac-
tice, the differences in clinical features, CSF and imaging
mean that distinguishing these is usually straightforward.
►► Post-­ictal MRI changes in patients with frequent seizures
can often mimic autoimmune encephalitis in the acute
phase.
►► Metabolic encephalopathies: usually delirium dominates
the clinical picture.
►► Hashimoto’s encephalopathy: fundamentally a difficult
diagnosis to make as definitions remain unclear. New
autoantibody discoveries may better describe many cases
once termed ‘Hashimoto’s’.34
Clinical management
Symptomatic considerations
In addition to treatment of the underlying immunolog-
ical process, it is often necessary to consider manage-
ment of seizures, movement disorders, behaviour,
pain, sleep and autonomic disturbance, and mood
disorders. We do not discuss this substantial topic
comprehensively here but rather we focus on special
considerations relevant to the two most common
forms of autoimmune encephalitis: NMDAR-­antibody
and LGI1-­antibody encephalitis.
The overlap in clinical features between NMDAR-­
antibody encephalitis and neuroleptic malignant
syndrome has led some to hypothesise that patients
with NMDAR-­ antibody encephalitis have hypersen-
sitivity to neuroleptic agents, with an increased risk
of developing neuroleptic malignant syndrome.35–38
Hence, we judiciously use antipsychotic medications
for behavioural symptom management, injury preven-
tion and to facilitate care, often once daily olanzapine
10 mg. Alternatively, we find benzodiazepines are effec-
tive, although often at high doses (sometimes up to 180
mg/day of diazepam), for treating both behavioural
symptoms and some dyskinesias.39 We frequently liaise
closely with neuropsychiatry colleagues to manage
behavioural features.
As discussed earlier, seizures are a common
presenting feature among the autoimmune encephalitis
Uy CE, et al. Pract Neurol 2021;21:412–423. doi:10.1136/practneurol-2020-002567

syndromes. However, from 103 patients with LGI1-­
antibody encephalitis, antiseizure medications alone
stopped faciobrachial dystonic seizures in only 10%.
By contrast, faciobrachial dystonic seizures stopped
within 30 days of starting immunotherapy in 51%,
rising to 88% by 90 days.40 The same principle
appears increasingly true for seizures associated with
multiple forms of autoimmune encephalitis.41 Thus,
it is imperative for appropriate and timely treatment
to recognise an underlying autoimmune encephalitis
syndrome. Furthermore, patients with LGI1-­antibody
disease are at higher risk of cutaneous reactions and
Stevens-­Johnson syndrome with antiseizure medica-
tions. Therefore, not only is antiseizure medication
use likely to be ineffective but may also result in iatro-
genic adverse events. Whenever possible, we prioritise
optimisation of immunotherapy in these patients and
increasingly reserve antiseizure medications only for
generalised convulsions or instances where the seizure
semiology is likely to cause injury.
After improvements on immunotherapy, discussed
later, patients often ask about the risk of ongoing
seizures. Indeed, epilepsy is defined as a tendency to
enduring seizures. So, it is of interest that few patients
in recent autoimmune encephalitis cohorts developed
epilepsy after the acute illness.41 42 This observation
suggests lifelong antiseizure therapy may not be neces-
sary in many cases. In seizure-­free patients keen to stop
antiseizure medications, we discuss a trial of weaning
including the possible complications of long-­term anti-
seizure medications (eg, osteoporosis, patient choice)
and implications for driving.
Early immunotherapy improves outcomes
The importance of early recognition and diagnosis
in autoimmune encephalitis is paramount to the ulti-
mate goal of optimal immunotherapy. Although there
are no specific data available for all autoantibody-­
mediated encephalitis syndromes, the two most
common forms of autoimmune encephalitis are clear
exemplars where improved patient outcomes associate
with early immunotherapy. In LGI1-­antibody enceph-
alitis, ~80% of patients noticed that faciobrachial
dystonic seizures typically precede onset of marked
cognitive impairment. Given that immunotherapy is
more effective than antiseizure medications in treating
LGI1-­ antibody-­
associated seizures, early treatment
with immunotherapy has shown great promise for
preventing otherwise incipient cognitive impairment
and functional disability.40 In NMDAR-­ antibody
encephalitis, early treatment independently predicted
good outcome (modified Rankin score ‍ 2 ‍ ) whereas
delays in immunotherapy of >4 weeks were associated
with poor functional outcomes at 1 year.43 44
In NMDAR-­antibody encephalitis, teratoma removal
is a key step in both acute treatment and relapse
prevention.43 It is considered of equivalent efficacy
to other individual first-­line immunotherapies, likely
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Review
because the teratoma is a germinal centre harbouring
NMDAR-­reactive B cells.45 Men and children tend to
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have non-­paraneoplastic disease. Half of adult female
patients are diagnosed with ovarian teratomas. So,
especially in these cases, pelvic imaging should be
performed, and small or equivocal findings carefully
followed up and investigated thoroughly. Repeat serial
imaging may be considered in cases where a teratoma
is suspected and a clinical relapse should certainly
prompt re-­investigation. We are familiar with patients
in whom the teratoma has been radiologically (mis-­)
interpreted as a luteal or haemorrhagic cyst. However,
overall, most patients do not have a detectable tera-
toma, meaning that in all cases immunotherapy should
not be delayed. Also, in our experiences, empirical
oophorectomy is low yield for a microscopic teratoma.
There are several options for acute and long-­term
immunotherapies in both the inpatient and outpa-
tient settings (table 2). Initial inpatient therapy often
involves corticosteroids, intravenous immunoglobulins
and/or plasma exchange. While awaiting autoantibody
results, we start first-­line immunotherapy when we are
clinically confident of the diagnosis. Second-­line ther-
apies include rituximab, cyclophosphamide and other
corticosteroid-­sparing agents. Choice of initial therapy
should balance the risk profile of the intervention
and the severity/trajectory of the individual patient’s
disease course.
In our experience, intravenous corticosteroids are
generically highly effective agents, so relative contra-
indications (eg, pre-­ existing diabetes or psychiatric
diseases) are often carefully managed in the acute phase
but rarely considered absolute contraindications. We
also find plasma exchange to be very effective, often
used if patients show a limited or inadequate response
to corticosteroids, or for patients with a rapid deteri-
oration whose trajectory may otherwise be intensive
care unit admission. While intravenous immunoglob-
ulin is the only immunotherapy with randomised data
to support its use,46 in practice it appears the least
effective of the three conventional first-­line interven-
tions. This observation is supported by the minimal
effect size observed in this inaugural randomised
control trial.
Below, we discuss our more specific management
approaches to the two most common autoantibody-­
mediated syndromes.
NMDAR-antibody encephalitis
Due to its associated high-­ morbidity and mortality,
potential for months of hospitalisation and high rate of
relapses, we favour early aggressive therapy in patients
with NMDAR-­ antibody encephalitis. Teratoma
removal and first-­ line immunotherapies are routine
interventions: typically, 3–5 days of 1 g intravenous
methylprednisolone daily, plus plasma exchange.
Second-­line immunotherapies reduce the relapse risk
and, from our clinical observations, expedite recoveries
7 of 14
8 of 14
Table 2  Immunotherapeutic options for treatment of autoimmune encephalitis
Immunotherapy Mechanism of action
First-­line therapy
Corticosteroids Multiple: largely via attenuation of immune
response via genomic and non-­genomic effects. daily×3–5 days.
Intravenous immunoglobulin Very wide to include modulation of T/B-­cells,
(IVIG) cytokines and innate pathways.
Blockade of variable domain of causative
antibodies by anti-­idiotype antibodies.
Plasmapheresis Bulk removal of circulating immunoglobulins.
Rebound state may increase susceptibility
of circulating antibody-­secreting cells
and precursors to cytotoxic therapies (ie,
cyclophosphamide).
Second-­line therapy
Mycophenolate Active metabolite (mycophenolic acid) inhibits Initially 500 mg two times a day,
inosine-5´-monophosphate dehydrogenase,
depletes guanosine nucleotides preferentially in maintenance.
T and B lymphocytes.
Azathioprine Inhibition of purine synthesis via active
metabolites 6-­mercaptopurine and
6-­thioguanine.
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Monitoring/prophylactic adjunctive
Dose/regimen therapies Side-­effects
Methylprednisolone 1 g intravenous Clinical monitoring for steroids side
effects.
+/- Oral prednisone 1 mg/kg/day. Calcium, vitamin D±bisphosphonate
Slow steroid taper. therapy.
Proton pump inhibitor for long steroid
tapers.
When in combination with other
immunotherapy, consider prophylaxis
for Pneumocystis jirovecii.
2 g/kg intravenous divided over 3–5 Clinical monitoring for allergic
days. reactions, transfusion reactions,
aseptic meningitis.
3–5 sessions over 5–10 days. Clinical monitoring for hypotension,
catheter-­related complications
(thrombosis, infection, air embolism)
and anaphylaxis.
Monitoring for electrolyte
abnormalities throughout.
Before starting: screening for latent
targeting to 1–1.5 g two times a dayHBV, HCV.
CBC-­D weekly×1 month, q2weeks×2
months→monthly.
Electrolytes, Cr/GFR, ALT, AST, ALP,
GGT, bilirubin, albumin, INR monthly.
Initial 50 mg daily, increase by 50 CBC-­D weekly×1 month, q2 weeks×2
mg increments q1-2 weeks until 2 to months→monthly.
3 mg/kg/day maintenance. ALT, AST, GGT, ALP, bilirubin, albumin,
INR q3months.
Age-­related cancer screening and skin
checks.
Consider testing for thiopurine S-­
methyltransferase (TMPT) deficiency
before initiation.
Review
Sleep disruption, irritability, osteoporosis, weight
gain, hypertension, hyperglycaemia, increased
intraocular pressures, upper gastrointestinal
bleeding, skin thinning/bruising/ striae,
reactivation of chronic infection, suppression
of endogenous steroid production,. Rare
complications include: avascular necrosis of jaw
or hip, P. jirovecii pneumonia.
Transfusion reactions (most mild), rare
complications include aseptic meningitis,
anaphylaxis, acute renal failure, haemolytic
anaemia and thromboembolism.
Mortality 3–5 per 10 000, hypocalcaemia,
hypokalaemia, metabolic alkalosis, hypotension,
catheter-­related complications (thrombosis,
infection, air embolism), anaphylaxis, TRALI and
rare viral transmission
Increased infection risk including reactivation
of viral infections (herpes simplex/zoster,
polyomavirus (BK virus) associated nephropathy
(PVAN), PML and CMV viraemia), increased risk of
lymphoma and skin malignancy, cytopenias.
GI toxicity, dose-­related cytopenias,
hepatotoxicity, increased infection rates, increased
risk of malignancy (including the rare entity
hepatosplenic T-­cell lymphoma (HSTCL), PML.
Continued
 Table 2  Continued
Monitoring/prophylactic adjunctive
Immunotherapy Mechanism of action Dose/regimen therapies Side-­effects
Rituximab Monoclonal antibody against CD20: principally Induction: 375 mg/m2 intravenous
Preinitiation: CBC+differential, ALT, Mild transfusion-­related reactions (headache,
B cell depletion. weekly×4 weeks or 500 mg AST, LDH, bilirubin, electrolytes, fever, chills, nausea), hypotension, anaphylaxis
intravenous×2 doses separated by
creatinine, screening for latent HBV, (rare), reactivation of latent infection (TB,
2 weeks. HCV, syphilis, HIV, and TB. hepatitis B).
Monthly postinfusion bloodwork
(starting 1-­week post-­induction):
CBC-­D, ALT, AST, LDH, bilirubin,
electrolytes, Cr.
Cyclophosphamide Induction of DNA cross-­linking and apoptosis by 750 mg/m2 intravenous monthly for CBC, HIV, HBV, HCV, VZV, Cytopenias (neutropenia most common), nausea/

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active metabolite (phosphoramide mustard). 3–6 months. liver enzymes, electrolytes, vomiting, diarrhoea, hair loss, mucocutaneous
creatinine+urinalysis weekly for the ulceration, haemorrhagic cystitis, infertility,
first 4 weeks, then q 2 weekly for next teratogenicity.
2 months→monthly.
Third-­line/experimental
Tocilizumab Monoclonal antibody against IL-6, blocking Initial: 4 mg/kg intravenous infusion. Preinitiation screening for TB. Fever response and CRP elevation may
binding to IL-6 receptor and preventing IL-6 May increase to 8 mg/kg based on Clinical monitoring for infection. be blunted by impairment in IL-6 receptor
mediated inflammatory cascade. response. Regular monitoring of blood counts, signalling. Hepatotoxicity, cytopenias, blood lipid
liver profile and lipids. abnormalities, immunosuppression.
Bortezimib Small-­molecule proteasome inhibitor. Relatively      Peripheral neuropathy, myalgia, diarrhoea
selective depletion of plasma cells due to high
immunoglobulin synthesis rate.
Sources: Sun et al, Shin et al,2 62 63 Joint Formulary Committee.
ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase; CBC-­D, complete blood count with differential; CD, cluster of differentiation; Cr, creatinine; CRP, C reactive protein; GFR, glomerular
filtration rate; GGT, gamma-­glutamyltransferase; HBV/HCV, hepatitis B/C virus; HIV, human immunodeficiency virus; HTLV, human T-­lymphotrophic virus; IL, interleukin; TB, tuberculosis; TRALI, transfusion associated lung
injury.
Review

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 Review
and time to discharge.43 Our threshold to escalate to
second-­line therapy is increasingly low, with >70%
of our patients receiving cyclophosphamide or ritux-
imab if awareness and behaviour have not improved
within 2 weeks. As outpatients, we tend not to employ
a prolonged course of oral corticosteroids, especially
if second-­line therapy or tumour removal appears to
be having the desired effect. This approach appears
to associate with a <5% rate of relapses, to date.
If second-­ line immunotherapy is not administered
during initial episode, it should be strongly considered
in relapses.
LGI1-antibody encephalitis
For this condition, we favour first-­line treatment with
high-­dose intravenous or oral corticosteroids. We have
an increasingly low threshold for plasma exchange
at disease onset, particularly in patients with greater
degrees of impairment. In our experience, oral pred-
nisolone should be maintained for around 24–36
months, as shorter durations of corticosteroids are
often associated with relapses.14 We typically taper
oral prednisolone from 50 to 60 mg for the first 2–4
months to around 20–30 mg by 12 months, with a
slow taper thereafter. In elderly patients, this approach
does inevitably induce some glucocorticoid side effects
that need to be carefully considered. However, in
our experience, despite corticosteroid-­sparing agents
(mainly mycophenolate mofetil) more rapid steroid
tapers tend to result in relapse. A few patients who
require cyclophosphamide show variable outcomes.
By contrast, rituximab appears more effective but
longer-­term follow-­up is awaited.
Molecular discoveries provide clinical
insights
The ability to detect CNS-­directed autoantibodies that
target the extracellular domains of neuroglial proteins
has revolutionised our ability to diagnose and classify
this nascent group of autoantibody-­ mediated disor-
ders. The confident detection of a causative autoan-
tibody has implications for the treatment regimen
and may help focus a search for associated malig-
nancies or surveillance for associated complications.
Moreover, an understanding of the basic immunobi-
ology helps to appreciate nuances around diagnostic
testing, suspected mechanisms of pathogenesis and
offer a rationale for administration of therapies. As
these diseases are associated with pathogenic autoan-
tibodies, a focus on the B cell immunobiology may be
the key to understanding autoimmune encephalitis. A
full discussion of the underlying immunopathology
is beyond the scope of this review and have been
described elsewhere.2 Here, we discuss select concepts
with the greatest clinical relevance.
Therapeutic insights
Autoantigen-­specific B cells are probably first estab-
lished peripherally before migrating into the CNS, as
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the pathogenic neuronal autoantibodies typically have
~50-­fold higher concentrations in the serum than in
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CSF.2 Interestingly, this ratio holds true for patients in
whom an infectious encephalitis (HSV encephalitis) is
followed by an autoimmune form (NMDAR-­antibody
encephalitis). Therefore, even with a brain-­ specific
trigger, the autoimmunity probably begins outside the
CNS. Hence, the peripheral B cells that carry these
self-­reactivities need to evade tolerance checkpoints,
a potential avenue for therapeutic interventions. Also,
the B lineage cells that secrete these autoantibodies in
the periphery are themselves a key therapeutic target.
For example, studies that implicate CD20− long lived
plasma cells as dominant producers of autoantibodies
imply drugs such as bortezomib—by acting on the
proteosome, which is especially active in plasma cells—
may be effective treatments.47 Alternatively, emerging
evidence suggests autoantibodies secreted by CD20+ B
cells that have undergone recent germinal centre reac-
tions may be a key source of these autoantibodies45 48:
if this mechanism were dominant, rituximab adminis-
tration might logically prove to be an especially effec-
tive option.
A key factor in generating the mature antigen-­
specific B cells is their interaction with antigen-­specific
T cells. This occurs via the engagement of human
leucocyte antigen (HLA) with the T-­ cell receptor.
Hence, it remains of biological interest that >90%
of patients with LGI1-­ antibodies carry the HLA-­
DRB1*07:01 allele, and that ~70% of the patients
with CNS diseases and CASPR2-­antibodies carry the
HLA-­DRB1*11:01 allele.49 T-­ cell directed therapies
may be a future avenue for treatment in these patients.
In addition, these findings may be of value in clinical
practice: we have found the absence of these alleles
as a useful adjunctive investigation to identify the few
patients with LGI1-­antibodies or CASPR2-­antibodies
who do not have an immunotherapy-­ responsive
syndrome. Hence, genetic testing may become a
reflexive test in these conditions.
After B cell autoreactivities originate in the periphery,
autoantibody access to the CNS is likely to play a
major role in pathogenesis. Of course, fundamentally,
the autoantibodies must gain access to the brain. But
it remains poorly addressed as to whether they cross
the blood–brain barrier as soluble immunoglobulins or
are predominantly secreted by intrathecal B cells that
have crossed the blood–brain barrier. In beginning to
address this, recent studies show these patients have an
enrichment of autoantigen-­reactive B cells in the CSF,
providing direct evidence of intrathecal autoantibody
production.50 51 Hence, drugs that prevent lympho-
cyte transmigration into the CNS may yet be effective
agents in these disorders.
Diagnostics insights
In addition, the biology around roles of peripheral
and central compartments also has implications for
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Figure 2  Neuronal surface antibody detection methods.
Current research and diagnostic methods expose the test
sample to neuronal antigens which differ in the properties
of the antigens. Cell-­based assays aim largely to expose a
single known antigen, by its expression in mammalian cells.
Conversely, neurone-­based assays and tissue-­based assays
expose multiple endogenous antigens, both those known
to be targets of pathogenic antibodies and as yet unknown
antigens. Additionally, the assays vary on whether the antigen
was fixed before incubation with the patient sample (serum or
cerebrospinal fluid) and whether the cell membrane is intact
(‘live’). Live cell-­based assays and live neurone-­based assays
neither fix the surface antigen nor permeabilise the membrane
before exposure to the patient’s sample. By contrast, in fixed
permeabilised cell-­based assays and tissue-­based assays, target
antigens are potentially altered by fixation and cell membrane
integrity is lost. Figure modified from Ramanathan et al.3 CBA,
cell-­based assay.
diagnostic testing. Autoantibodies can be detected in
both CSF and serum, and—put simply—both samples
should be sent in all patients, wherever possible.
However, there are important nuances between condi-
tions. For example, LGI1-­antibodies are not detected
in around 50% of patient CSF samples.33 By contrast,
NMDAR-­antibodies are consistently detected in the
CSF of patients and said to be absent in ~20% of
serum samples. Finding autoantibodies in the CSF
but not the serum does not seem biologically intu-
itive given the immunological response likely begins
in the periphery, perhaps most clearly in patients with
(systemic) ovarian teratomas. By comparison to serum,
CSF has a ~500-­fold lower total IgG concentration
and hence offers a sample with inherently lower back-
grounds in diagnostic assays, which may explain the
above finding. Yet, in some patients, for example,
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Review
those who are irritable, not suitable for sedation and
in young children, serum may be the only pragmatic
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sample source. However, serum NMDAR-­antibodies
occur at ~3% rates in healthy and disease controls and
hence so called ‘clinically irrelevant’ serum NMDAR-­
antibody results are not infrequent, again supporting
the use of CSF for detecting NMDAR-­antibodies. For
these reasons, in this condition, the absence of CSF
positivity is considered to indicate a lack of direct
autoantibody pathogenicity. However, as described
above, the opposite is true for LGI1-­antibodies. There-
fore, whenever possible, paired CSF-­serum should be
tested.
When sending and interpreting results for CNS
autoantibody testing, it is important to emphasise
the clinical hypothesis. Clinicians interpreting these
results should also take into account differences in
sensitivity and specificity of individual autoantibody
tests (figure 2). For example, several clinical labora-
tories use commercially available ‘fixed’ cell-­ based
assay kits. These kits have limitations as they inher-
ently alter the native antigens with fixation, creating
non-­physiological autoantigens.3 By contrast, live cell-­
based assays detect autoantibodies against the closest
resemblance of the targets that would be encountered
in vivo. Live cell-­based assays are often more sensi-
tive than fixed ones52–54; therefore, in the setting of
an appropriate clinical syndrome, a negative test on
fixed cell-­based assay should raise suspicion of a false-­
negative result and clinicians should consider having
these samples re-­tested at a reference laboratory.
‘I’m sure this patient has an autoantibody’
We continue to see several patients with no known
autoantibody, but a clinical syndrome compatible with
autoimmune encephalitis. In these so called ‘seroneg-
ative’ cases, where there is a clinical suspicion of an
autoantibody but no identified defined autoantigenic
target, we aim to begin early immunotherapy when-
ever possible given that autoimmune encephalitis is a
treatable syndrome. In parallel, we continue to re-­eval-
uate possible alternative diagnoses but escalate therapy
when autoimmune encephalitis is considered the like-
liest cause.
Various research-­level tests can offer greater diag-
nostic clarity (figure 2).3 The patient sera/CSF can be
applied to rodent brain sections to identify neuroglial
reactivity and, perhaps, a distinctive binding pattern.
This approach has been used in several instances as
an initial step in target identification, but is also a
valuable technique to simply diagnose a brain reac-
tive autoantibody.55 As this method exposes patient
autoantibodies to both intracellular and extracellular
domains of neuroglial proteins, it does not exclusively
detect pathogenic species. To define these, it is possible
to assess reactivity of serum or CSF IgGs against the
surface of cultured neurones or astrocytes. While time
consuming to perform, binding patterns have provided
11 of 14
Review
valuable information for many patients with suspected
autoantibody-­mediated syndromes who were negative
on available clinical assays. These tests are available on
request from research laboratories.
Closing remarks
The recognition of neuronal surface autoantibodies as a
cause of encephalitis has had far-­reaching implications.
It has helped to define a group of immunotherapy-­
responsive disorders, describe their pathogenesis, and
develop therapies informed by these pathogenic mech-
anisms. Further, the scope of autoantibody-­mediated
diseases has expanded beyond the initial limbic
encephalitis picture to include other polysymptom-
atic immunotherapy-­ responsive syndromes. Clinical
suspicion of these disorders remains the cornerstone
to their detection and there are now many clinically
recognisable syndromes described. Interpretation of
autoantibody results should similarly be in the context
of this clinical picture. Earlier recognition, treatment
Further reading
►► Graus F, Titulaer MJ, Balu R, etal. A clinical
approach to diagnosis of autoimmune encephalitis.
Lancet Neurol 2016;15:391–404. doi:10.1016/
S1474-4422(15)00401-9.A.
►► Ramanathan S, Al-­Diwani A, Waters P, etal. The
autoantibody-­mediated encephalitides: from clinical
observations to molecular pathogenesis. J Neurol
2019;1–19. doi:10.1007/s00415-019-09590-9.
►► SunB, Ramberger M, O’Connor KC, etal. The B cell
immunobiology that underlies CNS autoantibody-­
mediated diseases. Nat Rev Neurol 2020;16:481–92.
doi:10.1038/s41582-020-0381-­z.
Key points
►► Autoimmune causes of encephalitis are at least
as common as infectious causes and should be
considered early.
►► Several characteristic core phenotypic manifestations
may strongly suggest an underlying autoantibody-­
mediated encephalitis; this should raise the
consideration of empiric immunotherapy once
infectious causes are reasonably excluded.
►► Early immunotherapy improves outcomes in patients
with autoimmune encephalitis.
►► Whenever possible, paired cerebrospinal fluid
and serum should be tested, and clinicians should
emphasise the clinical hypothesis when interpreting
the results.
►► Brain sections and neuronal cultures are valuable
methods to detect autoantibodies in patients who
have a suspected autoimmune condition despite
negative antigen-­specific results.
12 of 14
and escalation of immunotherapy in many of these
syndromes can lead to improved outcomes and
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reduced disability.
Twitter Sarosh R Irani @ANG_Oxford
Contributors  All authors contributed to the drafting, editing
and intellectually to this article.
Funding  SRI is supported by the Wellcome Trust
(104079/Z/14/Z), BMA Research Grants—Vera Down
grant (2013), Margaret Temple (2017), Epilepsy Research
UK (P1201), the Fulbright UK-­US commission (MS Society
research award) and by the NIHR Oxford Biomedical Research
Centre. This research was funded in whole, or in part, by
the Wellcome Trust [Grant number 104079/Z/14/Z]. For the
purpose of Open Access, the author has applied a CC BY
public copyright licence to any author accepted manuscript
version arising from this submission. SB has received salary
support from the NIHR and is currently supported by the
Wellcome Trust. CU is supported by the Friedman Award for
Health Scholars (University of British Columbia) and received
salary support from the UBC Division of Neurology. The
views expressed are those of the author(s) and not necessarily
those of the NHS, the NIHR, the Department of Health,
UBC or Vancouver Coastal Health. The funders had no role
in the preparation, review or approval of the manuscript; and
decision to submit the manuscript for publication.
Competing interests  SRI is a coapplicant and receives royalties
on patent application WO/2010/046716 (U.K. patent no.,
PCT/GB2009/051441) entitled ‘Neurological Autoimmune
Disorders’. The patent has been licensed commercially for the
development of assays for LGI1 and other VGKC-­complex
antibodies. SRI and SB are coapplicants on a patent application
entitled ‘Diagnostic Strategy to improve specificity of CASPR2
antibody detection’ (PCT/GB2019/051257, publication
number WO/2019/211633 and UK1807410.4). SRI has
received honoraria from UCB, MedImmun, ADC therapeutics
and Medlink Neurology, and research support from CSL
Behring, UCB and ONO Pharma. CU declares no competing
interests with respect to this publication.
Patient consent for publication  Obtained.
Provenance and peer review  Commissioned; externally peer
reviewed by Neil Anderson, Auckland, New Zealand, and
Anais Thouin, Newcastle-­upon-­Tyne, UK.
Open access  This is an open access article distributed in
accordance with the Creative Commons Attribution 4.0
Unported (CC BY 4.0) license, which permits others to copy,
redistribute, remix, transform and build upon this work for any
purpose, provided the original work is properly cited, a link
to the licence is given, and indication of whether changes were
made. See:  https://​creativecommons.​org/​licenses/​by/​4.​0/.
ORCID iDs
Christopher E Uy http://​orcid.​org/​0000-​0002-​0688-​6522
Sophie Binks http://​orcid.​org/​0000-​0003-​0991-​5998
Sarosh R Irani http://​orcid.​org/​0000-​0002-​7667-​9748
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